The present invention relates to bioresorbable polymeric compositions for use in the manufacture of medical devices, methods of making said compositions, medical devices made from said compositions and methods of treatment of the human or animal body involving such devices.
There is a need for surgical repair devices such as sutures, bone plates, interference screws, tissue fasteners, staples and other tissue and fracture fixation devices which are bioresorbable. Reference herein to a material being xe2x80x9cbioresorbablexe2x80x9d means that it breaks down over a finite period of time due to the chemical/biological action of the body. Preferably, complete resorption occurs within about 5 years, More preferably within about 3 years. This breakdown is at a rate allowing the repair device to maintain sufficient integrity while the soft tissue or bone heals: surgical repair devices formed of materials which are resorbed too quickly may fail when compressive, tensile or flexural loads are placed on them before the tissue or bone has fully healed. Advantages of using bioresorbable materials over non-bioresorbable materials, e.g. metals, are that they encourage tissue repair and further surgery is not required to remove them. In addition, there is the issue of stress-shielding: tissues like bone tend to grow well in regions where there is a prevalence of high stress. If the stress is reduced or removed, because, for example, an implant is bearing all the load, then the tissue may tend to recede around it resulting in loosening over the longer term. Implanted bioresorbable materials do not tend to give rise to adverse effects due to stress-shielding.
It is known to use certain bioresorbable polymeric materials, like polyglycolic acid (PGA) and polylactic acid (PLA), for manufacturing surgical devices. These have the disadvantage, however, that they are brittle.
In addition, it is known to form blends of these materials and others, e.g. polycaprolactone (PCL), polytrimethylene carbonate (PTMC) and polydioxanone (PDO), to achieve desired physical attributes, like melting point and mechanical properties. It can prove difficult, however, to achieve the desired bioresorption rate of such materials in vivo.
Reference is also made to U.S. Pat. No. 5,475,063, which teaches a blend of a bioresorbable random copolymer and another bioresorbable polymer. This is not only the stated aim of this document, but in all the examples manufacture of the copolymer is by non-sequential addition of the components, i.e. a random copolymer will result.
It is an object of the present invention to provide polymers, particularly for medical applications, with desirable mechanical and resorption properties.
According to a first aspect of the invention, a bioresobable polymeric composition is presented comprising a blend comprising a first bioresorbable polymer and a second, bioresorbable polymer, wherein the first bioresorbable polymer is a block copolymer.
Polymer blends are usually classified as either miscible or immiscible. Many combinations of polymers form immiscible blends, this being determined by a delicate balance of entropic and enthalpic forces of the blended polymers. The compatibility of two polymers in a mobile phase depends mainly on the forces acting between the various groups in the chains of the same material as well as between the groups in the chains of the two different materials. In non-polar or weakly polar polymers the physical forces acting are principally dispersion forces. Therefore, when two non-polar polymers in a mobile isotropic liquid state are mixed together in a blend, phase separation into a dispersed and a continuous phase usually occurs. This phase separation is referred to herein as xe2x80x9cmacrophase separationxe2x80x9d.
The physical behaviour of block copolymers is related to solid state morphology. Block copolymers sometimes exhibit phase separation which typically gives rise to a continuous phase consisting of one block type in a continuous matrix consisting of a second block type. In many applications, the dispersed phase consists of hard domains which are crystalline or glassy and amorphous, the matrix being soft and rubber-like. This phase separation is referred to herein as xe2x80x9cmicrophase separationxe2x80x9d. For more details regarding phase separation in block copolymers, reference is made to D. C. Allport and W. H. Janes, xe2x80x9cBlock Copolymersxe2x80x9d, Applied Science Publishers Ltd., London, 1973.
In a blend of a block copolymer and another polymer, it is possible to have microphase separation within the block copolymer itself and macrophase separation between the copolymer and the other polymer. Reference herein to microphase-separated copolymer implies that the dimensions of the domains are in the size range of less than or equal to 500 nm. Reference herein to macrophase separation implies domain sizes (i.e. domains of dispersed and continuous phases) in the size range of greater than or equal to 1 micron, unless a compatibiliser has been added, in which case the dimensions of the domains domain sizes are larger than 500 nm.
A blend of this type gives a large number of variables which may be altered, to allow the rate of bioresorption and desired mechanical properties to be precisely tailored to desired levels: not only may the second bioresorbable polymer and the at least two types of block of the first bioresorbable polymer be varied, but either polymer may form the dispersed or the continuous phase, providing even more scope for variation of the properties of the material.
As stated, the first bioresorbable polymer may form the dispersed phase or the continuous phase. Preferably, the first bioresorbable polymer forms the dispersed phase and the second bioresorbable polymer forms the continuous phase.
Advantageously, there is also microphase separation within the first bioresorbable polymer. This allows the possibility of selecting a block of the copolymer which resorbs relatively quickly, generating porosity and allowing tissue ingrowth. It also allows the possibility of having a further block of the copolymer which modifies the blend properties (e.g. toughens it).
Advantageously, the second bioresorbable polymer and each of the types of block of the first bioresorbable polymer have different resorption rates. This allows porosity to be generated by resorption in certain parts of the blend, but, at the same time, structural integrity to be maintained while this is occurring.
Most preferably, at least one of the types of block of the first bioresorbable polymer is selected to have a higher rate of resorption than both the other type(s) of block of said first bioresorbable polymer and the second bioresorbable polymer.
The first resorbable polymer is a copolymer, for example a diblock (i.e. AB), triblock (i.e. ABA) or multiblock (e.g. ABC or segmented) block copolymer.
The bioresorbable repeating units of the first bioresorbable polymer may be selected from saturated or unsaturated esters, including orthoesters, carbonates, anhydrides, amides, ethers, or saccharides.
Advantageously, the repeating units of the first bioresorbable polymer are derived from cyclic monomers capable of undergoing ring opening followed by polymerisation. Preferred cyclic monomers are cyclic esters and carbonates, like lactide (LA), glycolide (GA), caprolactone (CL), p-dioxanone (p-DO) and trimethylene carbonate (TMC). The ring opening reaction has the advantage that it may produce higher molecular weight polymers which may have superior mechanical and degradation properties. In addition, polyesters and polycarbonates have the advantage that they degrade in vivo to produce non-toxic by-products like carbon dioxide and water.
More preferably, the block copolymers comprise GA and/or TMC. Most preferably, the block copolymer is PGA-PTMC-PGA, which will also be referred to herein as Polyglyconate B and, in one form, as MAXON B(trademark). The PGA blocks degrade relatively rapidly in vivo to give porosity and allow tissue ingrowth, while the PTMC blocks provide rubber-toughening which helps maintain the structural integrity of the blended material.
According to an advantageous embodiment of this aspect of the invention, one of the types of block of the first biodegradable polymer has a glass transition temperature, Tg, above ambient temperature (about 25xc2x0 C.) and one has a glass transition temperature, Tg, below ambient temperature. Preferably, the block copolymer comprises an essentially rubber central block with a Tg below ambient temperature and semi-crystalline end blocks with a Tg above ambient temperature.
The first biodegradable polymer may be a linear or non-linear block copolymer or comprise linear and non-linear portions. If it is non-linear, it may be formed as a star, comb, graft, brush, hyperbranched or xe2x80x9chairyxe2x80x9d block copolymer or of mixtures thereof.
The weight average molecular weight (Mw) of the first biodegradable polymer of the present invention may be in the range 30,000 to 3,000,000. Preferably, it is in the range 50,000 to 1,000,000.
Advantageously, the first biodegradable polymer of the present invention has an inherent viscosity of between 0.5 and 4.0 dL/g.
The second biodegradable polymer of the present invention may be a homopolymer, block or random copolymer. It may be a linear or non-linear e.g. branched, star, brush, comb, graft, hyperbranched or xe2x80x98hairyxe2x80x99 polymer or mixtures thereof.
Preferably, the second biodegradable polymer is a resorbable aliphatic polyester or polycarbonate. Again, these materials have the advantage that the decomposition products are non-toxic. More preferably, it comprises repeating units incorporating one or more of the following monomers: GA,p-DO,LA,TMC and CL. Again, these cyclic monomers polymerise by ring opening to give high molecular weight polymers with superior mechanical and degradation properties. In addition, the second polymer may comprise hydroxybutyrate (HB) monomers.
Advantageously, the second biodegradable polymer biodegrades at a lower rate than the first biodegradable polymer, i.e. the second polymer is more resistant to hydrolytic degradation and holds its strength for longer than the first biodegradable polymer. The choice of the second biodegradable polymer can therefore be determined empirically once the first polymer has been chosen.
A particularly preferred second biodegradable polymer is PLA.
A highly preferred blend according to the present invention is PGA-PTMC-PGA with PLA.
The second biodegradable polymer may make up from 1 to 99% by weight of total composition of the final product. Preferably, it makes up 20% to 90% and even more preferably, 40% to about 90% by weight of the total composition of the final product.
The bioresorbable composition according to the present invention may optionally comprise a compatibiliser, i.e. a component that is effective at the interface between the continuous and dispersed phases of the macrophase to reduce the dispersed phase domain sizes. Advantageously, the compatibiliser is a polymer, preferably an AB block copolymer. Preferred polymers comprise repeating units incorporating at least one of the following monomers: GA, DO, LA, TMC, CL. It is particularly preferred that the compatilibilser comprise at least one repeating unit present in the first polymer and at least one repeating unit present in the second polymer.
Advantageously, the compatibiliser comprises from about 1 to about 10% by weight of the total composition, preferably less than 5% wt of the total composition. It is also preferred that the compatibiliser have a weight average molecular weight (MW) less than that of both the first and second polymers separately. This facilitates better interfacing of the compatibiliser between the dispersed and continuous phases. With this in mind, the compatibiliser preferably has an MW of less than 100,000, more preferably less than 50,000.
The blend of the present invention may further comprise an inorganic filler such as calcium based salts to improve the osteoconductivity of the final product. Suitable calcium-based salts include calcium carbonate in various forms, especially aragonite, calcium phosphate, calcium sulphate, hydroxyapatite, BIOGALSS(trademark) and the material 45S5(trademark) produced by MO-SCI Corp. The filler of the present invention may be in particle form. Preferably, the average particle size is less than 1 mm, more preferably, less than 200 microns. The blend of the present invention may comprise between about 10 to about 60% by volume of filler.
A second aspect of the invention relates to medical devices such as sutures, surgical fasteners, clips, sutures, staples, plates, screws e.g. interference screws, rods, pins and tapes, comprising the above-defined blends.
A third aspect of the invention relates to a surgical procedure comprising the step of incorporating a medical device, as defined above, into a tissue defect in a human or animal body.
A fourth aspect of the invention relates to methods of manufacture of the above-defined blends.
According to a first method, the first and second polymers are heated to form first and second polymer melts then said melts are blended. Optionally, said blend may be extruded, for example through a tapering die. The resulting blended workpiece may be subjected to one or more of the steps of granulation, drying and injection moulding to form a final product.
According to a second method, a solvent is selected in which both first and second polymers are soluble. The second polymer is added to said solvent and agitated until it is dissolved, at which point the first polymer, the block copolymer, is added to the solution and subjected to agitation. Suitably, agitation is carried out for up to one hour, preferably about 30 minutes. The solvent is then evaporated. Preferably, this is carried out in gradual stages involving one or both of natural evaporation and an evaporator, preferably a rotor evaporator. Finally, the blend is placed in a vacuum oven and heated to remove the residual solvent. Appropriate conditions for this are for a temperature of 80xc2x0 C. for about 2 hours.